Project Summary: Several neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, as well as the polyglutamine expansion diseases, result from protein misfolding and accumulation due to genetic and/or environmental causes. Spinal and bulbar muscular atrophy (SBMA) is an adult-onset, inherited neuromuscular disease that is caused by polyglutamine expansion within the androgen receptor (AR); it is related to other neurodegenerative diseases caused by polyglutamine expansion, including Huntington's disease and several spinocerebellar ataxias. Although the precise pathways leading to neuronal dysfunction and death are unknown, the evaluation of transgenic mouse and cell models of these diseases has yielded mechanistic insights into disease pathogenesis. SBMA stands apart from other polyglutamine diseases in that its onset and progression are dependent on AR androgenic ligands. Our cell and mouse models of SBMA reproduce the androgen- and polyglutamine-dependent nuclear AR aggregation seen in patients, as well as its consequent toxicity, making these models highly useful for the analysis of the mechanistic basis for upstream events involved in AR toxicity. Our long-term objectives are to use these models to develop a mechanistic understanding of hormone-dependent, polyglutamine-expanded AR toxicity. A growing body of evidence suggests that long polyQ tracts cause cellular dysfunction and ultimately cell death, at least in part by dysregulating protein-protein interactions that sustain normal cellular function. We have utilized a quantitative proteomics approach to identify changes in the AR protein interaction network caused by polyQ expansion in a cell model, and identified several protein candidates that may be involved in polyQ-expanded AR pathogenicity. Our preliminary studies on one of the identified interactors, USP7 (a preferential interactor with polyQ-expanded AR), reveals a role for USP7 in SBMA. We propose here to 1) carry out additional interactome screens in spinal cord and muscle tissues of a validated mouse model of SBMA, 2) investigate the roles of the other differentially interacting proteins identified in our initial screen, and 3) continue our mechanistic studies of the role of USP7 in SBMA. We anticipate that results from these studies will lead us to a deeper understanding of the molecular pathogenesis of SBMA, and will yield novel pathways amenable to therapeutic modulation for SBMA.